Role of Genetic Variations on MHC Class I Antigen-Processing Genes in Human Cancer and Viral-Mediated Diseases

Molecular Immunology 113 (2019) 11–15

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Molecular Immunology

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Role of genetic variations on MHC class I antigen-processing genes in human ☆ cancer and viral-mediated diseases T ⁎ Valerio D’Alicandroa, Paolo Romaniaa, Ombretta Melaiua,b, Doriana Frucia, a Immuno-Oncology Laboratory, Pediatric Haematology/Oncology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy b Department of Biology, University of Pisa, Pisa, Italy

ARTICLE INFO ABSTRACT

Keywords: Cytotoxic T lymphocytes constantly monitor peptide-MHC class I complexes on the cell surface to eliminate Single nucleotide polymorphism transformed and virally infected cells expressing peptides derived from abnormal proteins. The generation of MHC class I antigen processing antigenic peptides and their loading on MHC class I molecules is a multistep process involving diﬀerent mole- Tumor cules that constitute the so-called antigen processing and presentation machinery (APM). To avoid immune- Viral infection mediated elimination, human tumors and pathogens have adopted diﬀerent strategies including loss of MHC class I expression and dysregulation of APM genes and proteins. Here, we summarize recent knowledge on genetic variations in APM genes and their association with cancer development and viral-mediated diseases.

1. MHC class I antigen processing pathway insulin-degrading enzyme, Nardilysin and thimet oligopeptidase) (Geier et al., 1999; Parmentier et al., 2010; Kessler et al., 2011), before being The generation of antigenic peptides is central in the regulation of actively transported into the ER by the transporter associated with immune responses. Cytotoxic T lymphocytes (CTLs) recognize and antigen processing (TAP), an heterodimeric complex composed of two eliminate transformed and infected cells expressing on the cell surface members of the ATP-binding cassette transporter family, TAP1 and peptide bound to MHC class I molecules derived from aberrant proteins. TAP2 (Lehnert and Tampe, 2017). TAP proteins form a transmembrane To avoid immune-mediated elimination, tumors and viruses adopt pore in the ER membrane whose opening and closing depend on ATP different strategies, including the loss of their antigenicity through the binding and hydrolysis, respectively (Gorbulev et al., 2001). TAP effi- reduced expression of MHC class I or dysregulation of the antigen ciently transports peptides of 8–12 residues with hydrophobic or basic processing machinery (APM) components leading to the formation of C-terminal (Schumacher et al., 1994; Momburg et al., 1994). Peptides antigenic peptides. that do not fit the MHC class I binding groove are further trimmed in Antigenic peptides are generated from the proteolytic degradation the ER lumen by ER aminopeptidases, ERAP1 and ERAP2 (Fruci et al., of endogenous proteins in the cytosol and endoplasmic reticulum (ER) 2014). These enzymes have complementary functions by selecting by the concerted action of the proteasome and additional peptidases substrates according to their N-terminal residues and internal sequence. (Fig. 1)(Shastri et al., 2005). Proteasome is a multimeric complex ERAP1 prefers large hydrophobic residues, whereas ERAP2 trims po- containing a catalytic core and regulatory particles (Sijts and Kloetzel, sitively charged residues (Saveanu et al., 2005). They preferentially 2011). Inflammatory cytokines, including type I and type II interferon trim peptides up to 8 or 9 amino acids, to produce the mature MHC (IFN), induce expression of catalytic subunits, named low molecular class I-binding peptide (Chang et al., 2005). In the ER, nascent MHC weight protein (LMP) 2, LMP7, and LMP10, which replace the 20 S class I heavy chains are chaperoned by the calnexin-calreticulin system. proteasome’s subunits to form the immunoproteasome. This shift re- MHC class I heavy chains assemble with β2-microglobulin (β2m) to sults in the increased generation of peptides with basic and hydro- form heterodimers that are recruited by calreticulin in the peptide phobic residues at C-terminal, providing the optimal anchor residues loading complex (PLC), a transient multisubunit complex that co- for stable binding to MHC class I molecules (Gaczynska et al., 1993). ordinates peptide translocation into the ER and peptide loading into Peptides released by the proteasome (ranging from 4 to 25 residues) are MHC class I molecules (Blees et al., 2017). The structure of PLC, as rapidly broken down by cytosolic proteases (tripeptidyl peptidase II, recently determined by cryo-electron microscopy, consists of MHC class

☆ Invited Mini-Review for the Special Issue on the EMBO Workshop on Antigen Processing and Presentation. ⁎ Corresponding author at: Immuno-Oncology Laboratory, Paediatric Haematology/Oncology Department, Bambino Gesù Children's Hospital, IRCCS, Viale di San Paolo 15, Rome 00146, Italy. E-mail address: [email protected] (D. Fruci). https://doi.org/10.1016/j.molimm.2018.03.024 Received 28 August 2017; Received in revised form 11 January 2018; Accepted 29 March 2018 Available online 04 April 2018 0161-5890/ © 2018 Elsevier Ltd. All rights reserved. ’ V. D Alicandro et al. Molecular Immunology 113 (2019) 11–15

Fig. 1. Schematic diagram of MHC Class I antigen processing and presentation pathway. Proteins targeted to the proteasome (immunoproteasome if contains the catalytic subunits LMP2, LMP7, and LMP10) through ubiquitination are cleaved into peptides and further trimmed by cytosolic proteases. A fraction of these peptides are then transported into the ER through the TAP subunits. After initial association with calnexin, empty MHC class I heavy-chain/β2-microglobulin (MHC-I HC/ β2m) enters a multimeric peptide loading complex (PLC) comprising of TAP subunits, tapasin, calreticulin and ERp57. Peptides too long for binding MHC class I are further trimmed by ER aminopeptidases ERAP1 and ERAP2. Once loaded with peptide, MHC class I molecules are released from the PLC and exported via the trans- Golgi to the cell surface for presentation to circulating CTLs and NK cells.

I molecules and a set of accessory proteins including TAP1, TAP2, ta- carcinomas (Fellerhoff et al., 2011; Song et al., 2014; Ma et al., 2015). pasin, calreticulin and the thiol oxidoreductase ERp57 (Blees et al., Furthermore, LMP7-145 along with TAP2-379, has been considered a 2017). After the peptide binding, stable pMHC class I complexes travel risk factor for Human papillomavirus (HPV)16-associated esophageal to the cell surface through the Golgi apparatus to be recognized by carcinoma (Cao et al., 2005). dedicated receptors on CTLs and NK cells (Kelly and Trowsdale, 2017). A further evidence of the key role of APM components in suscept- Defects in the function and expression of each component of the ibility to HPV16-associated diseases is indicated by the different dis- APM, ultimately result in altered repertoire of antigenic peptides pre- tribution of SNPs of TAP1, TAP2 and tapasin (TAP1-458, TAP1-518, sented to CTLs and NK cells and different vulnerability to tumor de- TAP1-637, TAP2-386, TAP2-577 and tapasin-59) in cervical carcinoma velopment (Leone et al., 2013) and viral infections diseases (Schuren patients as compared to control groups, although no functional data et al., 2016). Herein we summarise recent knowledge on the genetic have been reported (Deshpande et al., 2008). Moreover, TAP1-648, variations in APM genes known to be associated with cancer and viral- located at a residue close to C-terminal to the functional signature motif mediated diseases. LSGGQ, typical of all ATP-binding cassette transporter family members (Logan et al., 1994; Li et al., 1996; Derand et al., 2002), has been as- 2. Genetic variations in APM genes and their predisposition to sociated with reduced expression of surface MHC class I in human colon cancer cancer (Yang et al., 2005). Functional analysis revealed that the TAP1- 648 Gln variant is associate with a reduced peptide translocation ac- Genetic variations of several APM genes are risk factors for many tivity as compared to the TAP1-648 Arg variant (Yang et al., 2005). types of cancer (Table 1). Furthermore, other authors identified two TAP1 SNPs, TAP1-333 and A recent meta-analysis identified two polymorphisms of LMP2 and TAP1-637, associated with high-grade cervical intraepithelial carci- LMP7 significantly associated with cancer risk in Asian population (Wu noma that remained significant even in women who were positive for et al., 2017). LMP2-60 showed a higher susceptibility to gynecological high-risk HPV types (Einstein et al., 2009). cancers, whereas LMP7-145 was associated to an increased risk of TAP1 and TAP2 polymorphisms have been investigated in patients gastrointestinal and gynecological cancers (Wu et al., 2017). LMP2-60 with hematological malignancies. The TAP1-333 G allele and the TAP2- and LMP10-151 have been considered risk factors for hematological 565 GA genotype were associated with multiple myeloma and chronic malignancies (Ozbas-Gerceker et al., 2013aa,b; Bruzzoni-Giovanelli lymphoid leukemia, respectively, whereas the TAP2-665 GG genotype et al., 2015). The prevalence of LMP2-60 AA genotype (Arg/Arg) was was considered a risk factor for both hematological malignancies significantly higher in acute myeloid leukemia patients and lower in (Ozbas-Gerceker et al., 2013ba,b). multiple myeloma patients, as compared to control groups (Ozbas- A SNP localized to the 5′ UTR of tapasin was associated with overall Gerceker et al., 2013aa,b), whereas LMP10-151 was significantly as- survival of colorectal cancer patients (Shao et al., 2013). The functional sociated with the risk of developing chronic myeloid leukemia consequences of this variant were not investigated so far, although its (Bruzzoni-Giovanelli et al., 2015). LMP7-145 Lys variant has been strategic location within histone marks (H3K27Ac, H3K9Ac and correlated with a reduced transcript stability and significantly asso- H3K4me3) and among binding sites for transcription factors (interferon ciated with an increased risk of ovarian, gastric and colorectal regulatory transcription factor 1 (IRF-1), IRF-2 and IRF-7) suggests its

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Table 1 Single nucleotide polymorphisms (SNPs) in APM genes associated with cancer.

Gene Name SNP Intron/ Exon Nucleotide change AA position* Major/Minor allele (AA) Tumor** Reference

LMP2 LMP2-60 rs17587 Exon 3 G/A 60 Arg/His AML,MM 18,19 LMP7 LMP7-145 rs2071543 Exon 2 C/A 49 Gln/Lys CRC,OC,GC,EC,CC 18,21-24,25, 29-33 LMP10 LMP10-151 rs14178 Exon 4 C/T 151 Gly/Gly CML 20 TAP1 TAP1-333 rs1057141 Exon 4 A/G 393 Ile/Val CIC,MM 30,31 TAP1-458 rs41550019 Exon 6 G/T 518 Val/Leu CC 25 TAP1-518 rs41561219 Exon 7 G/A 578 Val/Ile CC 25 TAP1-637 rs1135216 Exon 10 A/G 697 Asp/Gly CC,CIC 25,30 TAP1-648 rs1057149 Exon 10 G/A 708 Arg/Gln CRC 29 TAP2 TAP2-379 rs1800454 Exon 6 G/A 379 Val/Ile EC,CC 24,35 TAP2-386 rs2228397 Exon 6 G/T 386 Gly/Gly CC 25 TAP2-565 rs2228396 Exon 9 G/A 565 Ala/Thr CLL 31 TAP2-577 rs2228391 Exon 9 A/G 577 Met/Val CC 25 TAP2-651 rs4148876 Exon 12 C/T 651 Arg/Cys CC 33,35 TAP2-665 rs241447 Exon 12 A/G 665 Thr/Ala CLL,MM 31 Tapasin Tapasin-5UTR rs3106189 5’ UTR G/A –– CRC 32 Tapasin-59 rs45583737 Exon 2 G/T 59 Asp/Tyr CC 25 ERAP1 ERAP1-56 rs3734016 Exon 2 G/A 56 Glu/Lys CC 35 ERAP1-127 rs26653 Exon 2 G/C 127 Arg/Pro CC, NSCLC 33,34,36 ERAP1-276 rs26618 Exon 5 A/G 276 Ile/Met CC, NSCLC 34,36 ERAP1-528 rs30187 Exon 11 A/G 528 Lys/Arg CC, NSCLC 34,36 ERAP1-575 rs10050860 Exon 12 G/A 575 Asp/Asn CC 35 ERAP1-730 rs27044 Exon 15 C/G 730 Gln/Glu CC, NSCLC 33,36

* Amino acid position as referred to NCBI sequences (LMP2: NM_002800.4, LMP7: NM_148919.3, TAP1: NM_000593.5, TAP2: NM_000544.3, Tapasin: NM_003190.4, ERAP1: NM_001040458.1, ERAP2: NM_001130140.2). ** AML, Acute Myeloid Leukemia; CML, Chronic Myeloid Leukemia MM, Multiple Myeloma; CRC, Colorectal Cancer; OC, Ovarian Cancer; GC, Gastric Cancer; EC, Esophageal Cancer; CC, Cervical Carcinoma; CIC, Cervical Intraepithelial Carcinoma; CLL, Chronic Lymphoid Leukemia; NSCLC, Non Small Cell Lung Cancer. role in transcriptional gene regulation. A study in 1207 Chinese individuals with different Hepatitis C virus Several ERAP1 functional variants have been associated with (HCV) infection outcomes revealed that LMP2-60 SNP affects suscept- cancer. Mehta and colleagues identified two ERAP1 SNPs, ERAP1-127 ibility to HCV infection and viral clearance (Huang et al., 2014). In and ERAP1-730, significantly associated with increased risk of HPV- particular, subjects carrying LMP2-60 His variant had a decreased risk induced cervical cancer (Mehta et al., 2007). They estimated that 12% of HCV chronicity (Huang et al., 2014). LMP7-145 SNP is one of the of all cervical carcinoma cases are attributable to the occurrence of the host factors affecting IFN response in patients with chronic HCV haplotype combination consisting of four SNPs, the minor alleles at (Sugimoto et al., 2002). The distribution of LMP7-145 Lys variant was ERAP1-127 and ERAP1-730 loci (Pro and Glu, respectively) and the higher in patients who responded to IFN therapy than in non-responder, major alleles at the TAP2-651 and LMP7-145 loci (Arg and Gln, re- and it was considered an independent factor that affects the outcome of spectively) (Mehta et al., 2007). The same authors showed that geno- IFN therapy (Sugimoto et al., 2002). Among patients with a low viral type distributions at the ERAP1-56, ERAP1-127, ERAP1-276 and load, those carrying the LMP7-145 Lys variant had an even higher ratio ERAP1-528 were significantly associated with the presence of lymph of sustained response compared to patients with the LMP7-145 Gln node metastases and decreased overall survival in cervical carcinoma variant (Sugimoto et al., 2002). A stratified analysis between persistent patients (Mehta et al., 2009). Multivariate analysis performed on HCV infection patients and control subjects indicated that the combined ERAP1-56 and ERAP1-127 genotypes combined with prognostic factors, genotype Gln/Lys + Lys/Lys was associated to an increased suscept- revealed that the two SNPs are dependent predictors of survival (Mehta ibility to HCV infection (Cui et al., 2010). et al., 2009). More recently, the same authors showed that one specific LMP7-145, TAP1-637 and TAP2-651 were considered a risk factor haplotype, consisting of ERAP1-575, TAP2-379 and TAP2-651 loci, was for Hepatitis B virus (HBV) infection in Chinese population (Xu et al., significantly associated with cervical carcinoma risk in one of the two 2007). The distribution of LMP7-145 and TAP1-637 was statistically Indonesian populations studied, suggesting that the different associa- associated with outcome of HBV infection in Chinese patients with tion depends on the genetic background and differences in HPV type chronic HBV, as compared to individuals spontaneously recovered from distribution (Mehta et al., 2015). HBV infection and normal controls (Shi et al., 2011). Recently, genotype and haplotype frequencies of four ERAP1 SNPs, TAP variants were investigated in the Han population in north- ERAP1-127, ERAP1-276, ERAP1-528 and ERAP1-730, were compared eastern China affected by persistent HBV infection (Qiu et al., 2012). in non-small-cell lung carcinoma patients from two genetically distant The frequency of TAP1-637 Gly and TAP2-687 Gln variants was sig- populations, Chinese and Poles. A significant association was detected nificantly higher in persistently and chronic HBV-infected patients than for all SNPs in Chinese but not in Poles patients, suggesting that other in HBV spontaneously recovered subjects (Qiu et al., 2012). A higher genetic and environmental factors contribute to these associations (Yao frequency of the TAP2-651 Cys was detected between hepatocellular et al., 2016). carcinoma cases and HBV spontaneously recovered controls (Qiu et al., No genetic variation in the other APM genes, including calreticulin, 2012). The TAP2-379 Ile variant was significantly associated with in- calnexin, ERp57 and β2m, has been associated with cancer develop- creased susceptibility to HCV infection (Huang et al., 2015). ment. TAP variants have been involved in human immunodeficiency virus (HIV) and Measles infections. In particular, TAP1-333 GG and TAP1- 3. Genetic variations in APM genes and their predisposition to 637 GA genotypes were positively associated with HIV-Tubercolosis co- virus-mediated diseases infection (Sunder et al., 2011), suggesting their involvement as risk factors for developing Tubercolosis co-infection in HIV-positive in- Genetic variations in APM genes have been associated with the dividuals. Measles vaccine non-responders were more likely to be outcome of several viral infections (Table 2). homozygous at TAP2-665 than hyper-responders, while no association

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Table 2 Single nucleotide polymorphisms (SNPs) in APM genes associated with viral-mediated diseases.

Gene Name SNP Intron/Exon Nucleotide change AA position* Major/Minor allele (AA) Virus** Reference

LMP2 LMP2-60 rs17587 Exon 3 G/A 60 Arg/His HCV 37 LMP7 LMP7-145 rs2071543 Exon 2 C/A 49 Gln/Lys HBV,HCV 38-40,41 TAP1 TAP1-333 rs1057141 Exon 4 A/G 393 Ile/Val HIV-TB 44 TAP1-637 rs1135216 Exon 10 A/G 697 Asp/Gly HBV,HIV-TB 40-42,44 TAP2 TAP2-379 rs1800454 Exon 6 G/A 379 Val/Ile HCV 43 TAP2-651 rs4148876 Exon 12 C/T 651 Arg/Cys HBV 40,42 TAP2-665 rs241447 Exon 12 A/G 665 Thr/Ala MV 45 TAP2-687 rs241448 Exon 12 C/T 687 STOP/Gln HBV 42 Tapasin Tapasin-260 rs2071888 Exon 4 C/G 260 Thr/Arg HCV 45 Tapasin-intr rs9277972 Intron 3 A/T –– HCV 43 ERAP1 ERAP1-3UTR rs17481334 3’ UTR G/A –– HCMV 49 ERAP2 ERAP2-392 rs2549782 Exon 7 G/T 392 Lys/Asn HIV 47,48 ERAP2-intr rs2248374 Intron 10 A/G –– HIV 48

* Amino acid position as referred to NCBI sequences (LMP2: NM_002800.4, LMP7: NM_148919.3, TAP1: NM_000593.5, TAP2: NM_000544.3, Tapasin: NM_003190.4, ERAP1: NM_001040458.1, ERAP2: NM_001130140.2 and NR_137637.1 for rs2549782 and rs2248374, respectively). ** HCV, Hepatitis C Virus; HBV, Hepatitis B Virus; TB-HIV, Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) co-infection; MV, Measles Virus; HCMV, Human Cytomegalovirus. was detected between TAP1 polymorphisms and vaccine response indicative of their functional effect. Understanding their physiological (Hayney et al., 1997). functions will be useful to explain their interplay among the other APM Tapasin variants also contribute to the outcome of viral infections. components and improve the knowledge of complex human diseases as The tapasin-260 variant affects the outcome of HCV infection in sy- tumors and viral-mediated diseases. In this sense, the recent associa- nergy with polymorphisms at HLA-B locus. The authors found that the tions between functional ERAPs polymorphisms and autoimmune dis- tapasin-260 Arg variant was more frequently detected in resolvers than eases (Reeves et al., 2014; Lopez de Castro et al., 2016) have high- in chronic HCV infected individuals (Ashraf et al., 2013). In another lighted the interest in MHC class I antigen-processing pathway, study, the intronic Thr variant of tapasin was associated with an in- underlining how its modulation can be exploited for therapeutic pur- creased risk of HCV chronicity (Huang et al., 2015). poses. Two studies evaluated the role of ERAP2 SNPs in resistance to HIV-1 infection. In the first study, ERAP2-392 was genotyped in an Italian Confl ict of interest population of HIV-1-exposed seronegative (ESN) individuals and donors (Cagliani et al., 2010). The distribution of ERAP2-392 GG genotype was The authors declare no potential conflict of interest. significantly deviated from Hardy-Weinberg equilibrium in ESN subjects, but not in controls, suggesting a role in conferring resistance to Acknowledgments HIV-1 infection. In the second study, the authors performed a genotype analysis in 104 HIV-1 ESN individuals and 130 controls, and found that This work was supported by grants to D.F. from the Italian Ministry haplotype B ERAP2 harbouring the ERAP2-392 T allele and the ERAP2- of Health (PE-2011-02351866), and the Associazione Italiana Ricerca intron G allele conferred susceptibility to HIV infection (Biasin et al., sul Cancro (AIRC) (18495). 2013). Of note, the ERAP2-intron G allele determines the activation of a cryptic splice site in intron 10 and production of an alternative spliced References ERAP2 mRNA with an in frame-stop codon, which following a non- sense-mediated decay does not produce the expected truncated protein. Ashraf, S., Nitschke, K., Warshow, U.M., Brooks, C.R., Kim, A.Y., Lauer, G.M., Hydes, T.J., The authors confirmed that ERAP2 diplotype status, consisting of the Cramp, M.E., Alexander, G., Little, A.M., Thimme, R., Neumann-Haefelin, C., Khakoo, S.I., 2013. Synergism of tapasin and human leukocyte antigens in resolving hepatitis combination of ERAP2-392 Lys allele and ERAP2-intron A allele (en- C virus infection. Hepatology 58, 881–889. coding full-length ERAP2), conferred protection to HIV infection Biasin, M., Sironi, M., Saulle, I., de Luca, M., la Rosa, F., Cagliani, R., Forni, D., Agliardi, (Biasin et al., 2013). C., lo Caputo, S., Mazzotta, F., Trabattoni, D., Macias, J., Pineda, J.A., Caruz, A., fi ′ Clerici, M., 2013. Endoplasmic reticulum aminopeptidase 2 haplotypes play a role in Recently, we identi ed a SNP in the 3 UTR of the ERAP1 gene, modulating susceptibility to HIV infection. Aids 27, 1697–1706. which prevents ERAP1 targeting and degradation by HCMV miR- Blees, A., Januliene, D., Hofmann, T., Koller, N., Schmidt, C., Trowitzsch, S., Moeller, A., UL112-5p (Romania et al., 2017). Specifically, HCMV miRUL112-5p Tampe, R., 2017. Structure of the human MHC-I peptide-loading complex. Nature – binds the 3′ UTR of ERAP1 A variant, but not the 3′ UTR of ERAP1 G 551, 525 528. Bruzzoni-Giovanelli, H., Gonzalez, J.R., Sigaux, F., Villoutreix, B.O., Cayuela, J.M., variant and accordingly ERAP1 expression is reduced, both at RNA and Guilhot, J., Preudhomme, C., Guilhot, F., Poyet, J.L., Rousselot, P., 2015. Genetic protein levels, in HCMV-infected AA but not GG fibroblasts. Conse- polymorphisms associated with increased risk of developing chronic myelogenous – quently, HCMV-infected GG fibroblasts were more efficient in trimming leukemia. Oncotarget 6, 36269 36277. fi Cagliani, R., Riva, S., Biasin, M., Fumagalli, M., Pozzoli, U., Lo Caputo, S., Mazzotta, F., viral antigens and being lysed by HCMV-peptide-speci c CTLs. These Piacentini, L., Bresolin, N., Clerici, M., Sironi, M., 2010. Genetic diversity at en- data indicate that individuals carrying GG genotye are able to resolve doplasmic reticulum aminopeptidases is maintained by balancing selection and is HCMV infections more readily than AA individuals. associated with natural resistance to HIV-1 infection. Hum. Mol. Genet. 19, 4705–4714. Cao, B., Tian, X., Li, Y., Jiang, P., Ning, T., Xing, H., Zhao, Y., Zhang, C., Shi, X., Chen, D., Shen, Y., Ke, Y., 2005. LMP7/TAP2 gene polymorphisms and HPV infection in eso- 4. Concluding remarks phageal carcinoma patients from a high incidence area in China. Carcinogenesis 26, 1280–1284. In summary, we have discussed an up-to-date summary of the ge- Chang, S.C., Momburg, F., Bhutani, N., Goldberg, A.L., 2005. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” netic variations of APM genes associated with tumors and viral-infected mechanism. Proc. Natl. Acad. Sci. U. S. A. 102, 17107–17112. diseases. Although we do not have information about the functional Cui, Q., Zhang, Y., Su, J., Shi, C., Lei, N., Ding, K., Li, J., Yu, R., Wang, L., Wang, N., 2010. role for the majority of APM gene variants, the recurrent associations The association between the genetic polymorphisms of LMP2/LMP7 and the outcomes of HCV infection among drug users. J. Biomed. Res. 24, 374–380. observed with different tumors and viral-infected diseases are

14 ’ V. D Alicandro et al. Molecular Immunology 113 (2019) 11–15

Derand, R., Bulteau-Pignoux, L., Becq, F., 2002. The cystic fibrosis mutation G551D alters genetic variation in antigen-processing machinery components and association with the non-Michaelis-Menten behavior of the cystic fibrosis transmembrane conductance cervical carcinoma risk in two Indonesian populations. Immunogenetics 67, 267–275. regulator (CFTR) channel and abolishes the inhibitory Genistein binding site. J. Biol. Momburg, F., Roelse, J., Hammerling, G.J., Neefjes, J.J., 1994. Peptide size selection by Chem. 277, 35999–36004. the major histocompatibility complex-encoded peptide transporter. J. Exp. Med. 179, Deshpande, A., Wheeler, C.M., Hunt, W.C., Peyton, C.L., White, P.S., Valdez, Y.E., Nolan, 1613–1623. J.P., 2008. Variation in HLA class I antigen-processing genes and susceptibility to Ozbas-Gerceker, F., Bozman, N., Kok, S., Pehlivan, M., Yilmaz, M., Pehlivan, S., Oguzkan- human papillomavirus type 16-associated cervical cancer. J. Infect. Dis. 197, Balci, S., 2013a. Association of an LMP2 polymorphism with acute myeloid leukemia 371–381. and multiple myeloma. Asian Pac. J. Cancer Prev. : APJCP 14, 6399–6402. Einstein, M.H., Leanza, S., Chiu, L.G., Schlecht, N.F., Goldberg, G.L., Steinberg, B.M., Ozbas-Gerceker, F., Bozman, N., Gezici, S., Pehlivan, M., Yilmaz, M., Pehlivan, S., Burk, R.D., 2009. Genetic variants in TAP are associated with high-grade cervical Oguzkan-Balci, S., 2013b. Association of TAP1 and TAP2 gene polymorphisms with neoplasia. Clin. Cancer Res. 15, 1019–1023. hematological malignancies. Asian Pac. J. Cancer Prev. : APJCP 14, 5213–5217. Fellerhoff, B., Gu, S., Laumbacher, B., Nerlich, A.G., Weiss, E.H., Glas, J., Kopp, R., Parmentier, N., Stroobant, V., Colau, D., de Diesbach, P., Morel, S., Chapiro, J., van Johnson, J.P., Wank, R., 2011. The LMP7-K allele of the immunoproteasome exhibits Endert, P., Van den Eynde, B.J., 2010. Production of an antigenic peptide by insulin- reduced transcript stability and predicts high risk of colon cancer. Cancer Res. 71, degrading enzyme. Nat. Immunol. 11, 449–454. 7145–7154. Qiu, B., Huang, B., Wang, X., Liang, J., Feng, J., Chang, Y., Li, D., 2012. Association of Fruci, D., Romania, P., D’Alicandro, V., Locatelli, F., 2014. Endoplasmic reticulum ami- TAP1 and TAP2 polymorphisms with the outcome of persistent HBV infection in a nopeptidase 1 function and its pathogenic role in regulating innate and adaptive northeast Han Chinese population. Scand. J. Gastroenterol. 47, 1368–1374. immunity in cancer and major histocompatibility complex class I-associated auto- Reeves, E., Elliott, T., James, E., Edwards, C.J., 2014. ERAP1 in the pathogenesis of an- immune diseases. Tissue Antigens 84, 177–186. kylosing spondylitis. Immunol. Res. 60, 257–269. Gaczynska, M., Rock, K.L., Goldberg, A.L., 1993. Gamma-interferon and expression of Romania, P., Cifaldi, L., Pignoloni, B., Starc, N., D’Alicandro, V., Melaiu, O., Pira, G.L., MHC genes regulate peptide hydrolysis by proteasomes. Nature 365, 264–267. Giorda, E., Carrozzo, R., Bergvall, M., Bergstrom, T., Alfredsson, L., Olsson, T., Geier, E., Pfeifer, G., Wilm, M., Lucchiari-Hartz, M., Baumeister, W., Eichmann, K., Kockum, I., Seppala, I., Lehtimaki, T., Hurme, M.A., Hengel, H., Santoni, A., Cerboni, Niedermann, G., 1999. A giant protease with potential to substitute for some func- C., Locatelli, F., D’Amato, M., Fruci, D., 2017. Identification of a genetic variation in tions of the proteasome. Science 283, 978–981. ERAP1 aminopeptidase that prevents human cytomegalovirus miR-UL112-5p- Gorbulev, S., Abele, R., Tampe, R., 2001. Allosteric crosstalk between peptide-binding, Mediated immunoevasion. Cell Rep. 20, 846–853. transport, and ATP hydrolysis of the ABC transporter TAP. Proc. Natl. Acad. Sci. U. S. Saveanu, L., Carroll, O., Lindo, V., Del Val, M., Lopez, D., Lepelletier, Y., Greer, F., A. 98, 3732–3737. Schomburg, L., Fruci, D., Niedermann, G., van Endert, P.M., 2005. Concerted peptide Hayney, M.S., Poland, G.A., Dimanlig, P., Schaid, D.J., Jacobson, R.M., Lipsky, J.J., 1997. trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the en- Polymorphisms of the TAP2 gene may influence antibody response to live measles doplasmic reticulum. Nat. Immunol. 6, 689–697. vaccine virus. Vaccine 15, 3–6. Schumacher, T.N., Kantesaria, D.V., Heemels, M.T., Ashton-Rickardt, P.G., Shepherd, Huang, P., Dong, L., Lu, X., Zhang, Y., Chen, H., Wang, J., Zhang, Y., Su, J., Yu, R., 2014. J.C., Fruh, K., Yang, Y., Peterson, P.A., Tonegawa, S., Ploegh, H.L., 1994. Peptide Genetic variants in antigen presentation-related genes influence susceptibility to length and sequence specificity of the mouse TAP1/TAP2 translocator. J. Exp. Med. hepatitis C virus and viral clearance: a case control study. BMC Infect. Dis. 14, 716. 179, 533–540. Huang, P., Zhang, Y., Lu, X., Xu, Y., Wang, J., Zhang, Y., Yu, R., Su, J., 2015. Association Schuren, A.B., Costa, A.I., Wiertz, E.J., 2016. Recent advances in viral evasion of the MHC of polymorphisms in HLA antigen presentation-related genes with the outcomes of class I processing pathway. Curr. Opin. Immunol. 40, 43–50. HCV infection. PloS One 10, e0123513. Shao, J., Lou, X., Wang, J., Zhang, J., Chen, C., Hua, D., Mo, F., Han, X., Zheng, S., Lin, B., Kelly, A., Trowsdale, J., 2017. Introduction: MHC/KIR and governance of specificity. 2013. Targeted re-sequencing identified rs3106189 at the 5’ UTR of TAPBP and Immunogenetics 69, 481–488. rs1052918 at the 3’ UTR of TCF3 to be associated with the overall survival of col- Kessler, J.H., Khan, S., Seifert, U., Le Gall, S., Chow, K.M., Paschen, A., Bres-Vloemans, orectal cancer patients. PloS One 8, e70307. S.A., de Ru, A., van Montfoort, N., Franken, K.L., Benckhuijsen, W.E., Brooks, J.M., Shastri, N., Cardinaud, S., Schwab, S.R., Serwold, T., Kunisawa, J., 2005. All the peptides van Hall, T., Ray, K., Mulder, A., Doxiadis, I.I., van Swieten, P.F., Overkleeft, H.S., that fit: the beginning, the middle, and the end of the MHC class I antigen-processing Prat, A., Tomkinson, B., Neefjes, J., Kloetzel, P.M., Rodgers, D.W., Hersh, L.B., pathway. Immunol. Rev. 207, 31–41. Drijfhout, J.W., van Veelen, P.A., Ossendorp, F., Melief, C.J., 2011. Antigen proces- Shi, C., Qian, Y.H., Su, J., Luo, S.S., Gu, J., You, H., Cui, Q., Lin, Y.D., Dong, M.H., Yu, sing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes. Nat. R.B., 2011. Genetic variation in the LMP/TAP gene and outcomes of hepatitis B virus Immunol. 12, 45–53. infection in the Chinese population. Epidemiol. Infect. 139, 674–682. Lehnert, E., Tampe, R., 2017. Structure and dynamics of antigenic peptides in complex Sijts, E.J., Kloetzel, P.M., 2011. The role of the proteasome in the generation of MHC class with TAP. Front. Immunol. 8, 10. I ligands and immune responses. Cell. Mol. Life Sci. : CMLS 68, 1491–1502. Leone, P., Shin, E.C., Perosa, F., Vacca, A., Dammacco, F., Racanelli, V., 2013. MHC class I Song, L., Ma, N., Han, L., Yan, H., Yan, B., Yuan, Z., Cao, B., 2014. Association between antigen processing and presenting machinery: organization, function, and defects in LMP2/LMP7 genetic variability and the metastasis risk of ovarian cancer in Chinese tumor cells. J. Natl. Cancer Inst. 105, 1172–1187. women in Beijing. Hum. Immunol. 75, 239–244. Li, C., Ramjeesingh, M., Wang, W., Garami, E., Hewryk, M., Lee, D., Rommens, J.M., Sugimoto, Y., Kuzushita, N., Takehara, T., Kanto, T., Tatsumi, T., Miyagi, T., Jinushi, M., Galley, K., Bear, C.E., 1996. ATPase activity of the cystic fibrosis transmembrane Ohkawa, K., Horimoto, M., Kasahara, A., Hori, M., Sasaki, Y., Hayashi, N., 2002. A conductance regulator. J. Biol. Chem. 271, 28463–28468. single nucleotide polymorphism of the low molecular mass polypeptide 7 gene in- Logan, J., Hiestand, D., Daram, P., Huang, Z., Muccio, D.D., Hartman, J., Haley, B., Cook, fluences the interferon response in patients with chronic hepatitis C. J. Viral Hepat. 9, W.J., Sorscher, E.J., 1994. Cystic fibrosis transmembrane conductance regulator 377–384. mutations that disrupt nucleotide binding. J. Clin. Invest. 94, 228–236. Sunder, S.R., Hanumanth, S.R., Gaddam, S., Jonnalagada, S., Valluri, V.L., 2011. Lopez de Castro, J.A., Alvarez-Navarro, C., Brito, A., Guasp, P., Martin-Esteban, A., Sanz- Association of TAP 1 and 2 gene polymorphisms with human immunodeficiency Bravo, A., 2016. Molecular and pathogenic effects of endoplasmic reticulum ami- virus-tuberculosis co-infection. Hum. Immunol. 72, 908–911. nopeptidases ERAP1 and ERAP2 in mhc-I-associated inflammatory disorders: towards Wu, D.F.L.Y., Zhang, J.J., Li, X., Lu, Z.P., Shi, G.D., Yuan, H., Ge, Y.G., Wu, P.F., Wang, Y., a unifying view. Mol. Immunol. 77, 193–204. Jiang, K.R., Miao, Y., 2017. Association between LMP2/LMP7 genetic variability and Ma, X., Yang, C., Tang, R., Xu, Z., Zhang, Z., Wang, Y., Zhang, J., Yang, L.I., 2015. cancer susceptibility, especially among Asians: evidence from a meta-analysis. Association between LMP2 and LMP7 gene polymorphisms and the risk of gastric Oncotarget 8 (Jun. (37)), 62445–62453. cancer: a case-control study. Oncol. Lett. 10, 509–517. Xu, C., Qi, S., Gao, L., Cui, H., Liu, M., Yang, H., Li, K., Cao, B., 2007. Genetic poly- Mehta, A.M., Jordanova, E.S., van Wezel, T., Uh, H.W., Corver, W.E., Kwappenberg, K.M., morphisms of LMP/TAP gene and hepatitis B virus infection risk in the Chinese po- Verduijn, W., Kenter, G.G., van der Burg, S.H., Fleuren, G.J., 2007. Genetic variation pulation. J. Clin. Immunol. 27, 534–541. of antigen processing machinery components and association with cervical carci- Yang, T., Lapinski, P.E., Zhao, H., Zhou, Q., Zhang, H., Raghavan, M., Liu, Y., Zheng, P., noma. Genes Chromosomes Cancer 46, 577–586. 2005. A rare transporter associated with antigen processing polymorphism over- Mehta, A.M., Jordanova, E.S., Corver, W.E., van Wezel, T., Uh, H.W., Kenter, G.G., Jan presented in HLAlow colon cancer reveals the functional significance of the signature Fleuren, G., 2009. Single nucleotide polymorphisms in antigen processing machinery domain in antigen processing. Clin. Cancer Res. 11, 3614–3623. component ERAP1 significantly associate with clinical outcome in cervical carci- Yao, Y., Wisniewski, A., Ma, Q., Kowal, A., Porebska, I., Pawelczyk, K., Yu, J., Dubis, J., noma. Genes Chromosomes Cancer 48, 410–418. Zuk, N., Li, Y., Shi, L., Kusnierczyk, P., 2016. Single nucleotide polymorphisms of the Mehta, A.M., Spaans, V.M., Mahendra, N.B., Osse, E.M., Vet, J.N., Purwoto, G., Surya, ERAP1 Gene and risk of NSCLC: a comparison of genetically distant populations, I.G., Cornian, S., Peters, A.A., Fleuren, G.J., Jordanova, E.S., 2015. Differences in Chinese and Caucasian. Arch. Immunol. Ther. Exp. (Warsz) 64, 117–122.